Sulfonylpyrazoline carboxamidine derivatives as potent 5-HT6 antagonists were first disclosed in WO 2008/034863. Related (hetero)arylsulfonylpyrazoline carboxamidines with the same pharmacological activity were disclosed in WO 2009/115515. The synthetic routes disclosed in these applications have reasonable yields, but they are not ideally suited for synthesis on the scale required for drugs in clinical development, let alone on the scale required for marketed drugs.
The objective of the present invention was to develop a novel synthetic route to sulfonylpyrazoline carboxamidine derivatives with improved atom efficiency [Trost, B. M. Science 1991, 254, 1471; Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233] and higher yield compared to the known routes, employing readily available or accessible building blocks under mild reaction conditions, and limiting the use and release of harmful chemicals.